TY  - JOUR
A1  - Guth, Sabine
A1  - Hüser, Stephanie
A1  - Roth, Angelika
A1  - Degen, Gisela
A1  - Diel, Patrick
A1  - Edlund, Karolina
A1  - Eisenbrand, Gerhard
A1  - Engel, Karl-Heinz
A1  - Epe, Bernd
A1  - Grune, Tilman
A1  - Heinz, Volker
A1  - Henle, Thomas
A1  - Humpf, Hans-Ulrich
A1  - Jäger, Henry
A1  - Joost, Hans-Georg
A1  - Kulling, Sabine E.
A1  - Lampen, Alfonso
A1  - Mally, Angela
A1  - Marchan, Rosemarie
A1  - Marko, Doris
A1  - Mühle, Eva
A1  - Nitsche, Michael A.
A1  - Röhrdanz, Elke
A1  - Stadler, Richard
A1  - van Thriel, Christoph
A1  - Vieths, Stefan
A1  - Vogel, Rudi F.
A1  - Wascher, Edmund
A1  - Watzl, Carsten
A1  - Nöthlings, Ute
A1  - Hengstler, Jan G.
T1  - Contribution to the ongoing discussion on fluoride toxicity
JF  - Archives of Toxicology
N2  - Since the addition of fluoride to drinking water in the 1940s, there have been frequent and sometimes heated discussions regarding its benefits and risks. In a recently published review, we addressed the question if current exposure levels in Europe represent a risk to human health. This review was discussed in an editorial asking why we did not calculate benchmark doses (BMD) of fluoride neurotoxicity for humans. Here, we address the question, why it is problematic to calculate BMDs based on the currently available data. Briefly, the conclusions of the available studies are not homogeneous, reporting negative as well as positive results; moreover, the positive studies lack control of confounding factors such as the influence of well-known neurotoxicants. We also discuss the limitations of several further epidemiological studies that did not meet the inclusion criteria of our review. Finally, it is important to not only focus on epidemiological studies. Rather, risk analysis should consider all available data, including epidemiological, animal, as well as in vitro studies. Despite remaining uncertainties, the totality of evidence does not support the notion that fluoride should be considered a human developmental neurotoxicant at current exposure levels in European countries.
KW  - pharmacology/toxicology
KW  - occupational medicine/industrial medicine
KW  - environmental health
KW  - biomedicine, general
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-307161
SN  - 0340-5761
SN  - 1432-0738
VL  - 95
IS  - 7
ER  - 
TY  - JOUR
A1  - Wilson, Duncan
A1  - Ambler, Gareth
A1  - Lee, Keon-Joo
A1  - Lim, Jae-Sung
A1  - Shiozawa, Masayuki
A1  - Koga, Masatoshi
A1  - Li, Linxin
A1  - Lovelock, Caroline
A1  - Chabriat, Hugues
A1  - Hennerici, Michael
A1  - Wong, Yuen Kwun
A1  - Mak, Henry Ka Fung
A1  - Prats-Sánchez, Luis
A1  - Martínez-Domeño, Alejandro
A1  - Inamura, Shigeru
A1  - Yoshifuji, Kazuhisa
A1  - Arsava, Ethem Murat
A1  - Horstmann, Solveig
A1  - Purrucker, Jan
A1  - Lam, Bonnie Yin Ka
A1  - Wong, Adrian
A1  - Kim, Young Dae
A1  - Song, Tae-Jin
A1  - Schrooten, Maarten
A1  - Lemmens, Robin
A1  - Eppinger, Sebastian
A1  - Gattringer, Thomas
A1  - Uysal, Ender
A1  - Tanriverdi, Zeynep
A1  - Bornstein, Natan M
A1  - Ben Assayag, Einor
A1  - Hallevi, Hen
A1  - Tanaka, Jun
A1  - Hara, Hideo
A1  - Coutts, Shelagh B
A1  - Hert, Lisa
A1  - Polymeris, Alexandros
A1  - Seiffge, David J
A1  - Lyrer, Philippe
A1  - Algra, Ale
A1  - Kappelle, Jaap
A1  - Salman, Rustam Al-Shahi
A1  - Jäger, Hans R
A1  - Lip, Gregory Y H
A1  - Mattle, Heinrich P
A1  - Panos, Leonidas D
A1  - Mas, Jean-Louis
A1  - Legrand, Laurence
A1  - Karayiannis, Christopher
A1  - Phan, Thanh
A1  - Gunkel, Sarah
A1  - Christ, Nicolas
A1  - Abrigo, Jill
A1  - Leung, Thomas
A1  - Chu, Winnie
A1  - Chappell, Francesca
A1  - Makin, Stephen
A1  - Hayden, Derek
A1  - Williams, David J
A1  - Kooi, M Eline
A1  - van Dam-Nolen, Dianne H K
A1  - Barbato, Carmen
A1  - Browning, Simone
A1  - Wiegertjes, Kim
A1  - Tuladhar, Anil M
A1  - Maaijwee, Noortje
A1  - Guevarra, Christine
A1  - Yatawara, Chathuri
A1  - Mendyk, Anne-Marie
A1  - Delmaire, Christine
A1  - Köhler, Sebastian
A1  - van Oostenbrugge, Robert
A1  - Zhou, Ying
A1  - Xu, Chao
A1  - Hilal, Saima
A1  - Gyanwali, Bibek
A1  - Chen, Christopher
A1  - Lou, Min
A1  - Staals, Julie
A1  - Bordet, Régis
A1  - Kandiah, Nagaendran
A1  - de Leeuw, Frank-Erik
A1  - Simister, Robert
A1  - van der Lugt, Aad
A1  - Kelly, Peter J
A1  - Wardlaw, Joanna M
A1  - Soo, Yannie
A1  - Fluri, Felix
A1  - Srikanth, Velandai
A1  - Calvet, David
A1  - Jung, Simon
A1  - Kwa, Vincent I H
A1  - Engelter, Stefan T
A1  - Peters, Nils
A1  - Smith, Eric E
A1  - Yakushiji, Yusuke
A1  - Necioglu Orken, Dilek
A1  - Fazekas, Franz
A1  - Thijs, Vincent
A1  - Heo, Ji Hoe
A1  - Mok, Vincent
A1  - Veltkamp, Roland
A1  - Ay, Hakan
A1  - Imaizumi, Toshio
A1  - Gomez-Anson, Beatriz
A1  - Lau, Kui Kai
A1  - Jouvent, Eric
A1  - Rothwell, Peter M
A1  - Toyoda, Kazunori
A1  - Bae, Hee-Yoon
A1  - Marti-Fabregas, Joan
A1  - Werring, David J
T1  - Cerebral microbleeds and stroke risk after ischaemic stroke or transient ischaemic attack: a pooled analysis of individual patient data from cohort studies
JF  - The Lancet Neurology
N2  - Background
Cerebral microbleeds are a neuroimaging biomarker of stroke risk. A crucial clinical question is whether cerebral microbleeds indicate patients with recent ischaemic stroke or transient ischaemic attack in whom the rate of future intracranial haemorrhage is likely to exceed that of recurrent ischaemic stroke when treated with antithrombotic drugs. We therefore aimed to establish whether a large burden of cerebral microbleeds or particular anatomical patterns of cerebral microbleeds can identify ischaemic stroke or transient ischaemic attack patients at higher absolute risk of intracranial haemorrhage than ischaemic stroke.

Methods
We did a pooled analysis of individual patient data from cohort studies in adults with recent ischaemic stroke or transient ischaemic attack. Cohorts were eligible for inclusion if they prospectively recruited adult participants with ischaemic stroke or transient ischaemic attack; included at least 50 participants; collected data on stroke events over at least 3 months follow-up; used an appropriate MRI sequence that is sensitive to magnetic susceptibility; and documented the number and anatomical distribution of cerebral microbleeds reliably using consensus criteria and validated scales. Our prespecified primary outcomes were a composite of any symptomatic intracranial haemorrhage or ischaemic stroke, symptomatic intracranial haemorrhage, and symptomatic ischaemic stroke. We registered this study with the PROSPERO international prospective register of systematic reviews, number CRD42016036602.

Findings
Between Jan 1, 1996, and Dec 1, 2018, we identified 344 studies. After exclusions for ineligibility or declined requests for inclusion, 20 322 patients from 38 cohorts (over 35 225 patient-years of follow-up; median 1·34 years [IQR 0·19–2·44]) were included in our analyses. The adjusted hazard ratio [aHR] comparing patients with cerebral microbleeds to those without was 1·35 (95% CI 1·20–1·50) for the composite outcome of intracranial haemorrhage and ischaemic stroke; 2·45 (1·82–3·29) for intracranial haemorrhage and 1·23 (1·08–1·40) for ischaemic stroke. The aHR increased with increasing cerebral microbleed burden for intracranial haemorrhage but this effect was less marked for ischaemic stroke (for five or more cerebral microbleeds, aHR 4·55 [95% CI 3·08–6·72] for intracranial haemorrhage vs 1·47 [1·19–1·80] for ischaemic stroke; for ten or more cerebral microbleeds, aHR 5·52 [3·36–9·05] vs 1·43 [1·07–1·91]; and for ≥20 cerebral microbleeds, aHR 8·61 [4·69–15·81] vs 1·86 [1·23–2·82]). However, irrespective of cerebral microbleed anatomical distribution or burden, the rate of ischaemic stroke exceeded that of intracranial haemorrhage (for ten or more cerebral microbleeds, 64 ischaemic strokes [95% CI 48–84] per 1000 patient-years vs 27 intracranial haemorrhages [17–41] per 1000 patient-years; and for ≥20 cerebral microbleeds, 73 ischaemic strokes [46–108] per 1000 patient-years vs 39 intracranial haemorrhages [21–67] per 1000 patient-years).

Interpretation
In patients with recent ischaemic stroke or transient ischaemic attack, cerebral microbleeds are associated with a greater relative hazard (aHR) for subsequent intracranial haemorrhage than for ischaemic stroke, but the absolute risk of ischaemic stroke is higher than that of intracranial haemorrhage, regardless of cerebral microbleed presence, antomical distribution, or burden.
Y1  - 2019
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-233710
VL  - 18
ER  -